Heparin binding-epidermal growth factor-like growth factor for the regeneration of chronic tympanic membrane perforations in mice

Tissue Eng Part A. 2015 May;21(9-10):1483-94. doi: 10.1089/ten.TEA.2014.0474. Epub 2015 Mar 17.


We aim to explore the role of epidermal growth factor (EGF) ligand shedding in tympanic membrane wound healing and to investigate the translation of its modulation in tissue engineering of chronic tympanic membrane perforations. Chronic suppurative otitis media (CSOM) is an infected chronic tympanic membrane perforation. Up to 200 million suffer from its associated hearing loss and it is the most common cause of pediatric hearing loss in developing countries. There is a need for nonsurgical treatment due to a worldwide lack of resources. In this study, we show that EGF ligand shedding is essential for tympanic membrane healing as it's inhibition, with KB-R7785, leads to chronic perforation in 87.9% (n=58) compared with 0% (n=20) of controls. We then show that heparin binding-EGF-like growth factor (5 μg/mL), which acts to shed EGF ligands, can regenerate chronic perforations in mouse models with 92% (22 of 24) compared with 38% (10 of 26), also with eustachian tube occlusion with 94% (18 of 19) compared with 9% (2 of 23) and with CSOM 100% (16 of 16) compared with 41% (7 of 17). We also show the nonototoxicity of this treatment and its hydrogel delivery vehicle. This provides preliminary data for a clinical trial where it could be delivered by nonspecialist trained healthcare workers and fulfill the clinical need for a nonsurgical treatment for chronic tympanic membrane perforation and CSOM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biocompatible Materials / chemistry
  • Chronic Disease
  • Disease Models, Animal
  • Drug Delivery Systems
  • ErbB Receptors / metabolism
  • Eustachian Tube / drug effects
  • Eustachian Tube / pathology
  • Eustachian Tube / physiopathology
  • Evoked Potentials, Auditory, Brain Stem / drug effects
  • Glycine / analogs & derivatives
  • Heparin-binding EGF-like Growth Factor / pharmacology
  • Heparin-binding EGF-like Growth Factor / therapeutic use*
  • Hydroxamic Acids
  • Ligands
  • Male
  • Mice
  • Otitis Media, Suppurative / drug therapy
  • Otitis Media, Suppurative / pathology
  • Otitis Media, Suppurative / physiopathology
  • Otoacoustic Emissions, Spontaneous / drug effects
  • Polymers / chemistry
  • Regeneration / drug effects*
  • Tympanic Membrane Perforation / drug therapy*
  • Tympanic Membrane Perforation / pathology
  • Tympanic Membrane Perforation / physiopathology*


  • Biocompatible Materials
  • Heparin-binding EGF-like Growth Factor
  • Hydroxamic Acids
  • KB R7785
  • Ligands
  • Polymers
  • ErbB Receptors
  • Glycine